Background/Purpose:

TNF and IL-17A are proinflammatory cytokines critically involved in the pathogenesis of psoriatic arthritis (PsA). Currently, targeting TNF is the first choice of a biologic disease-modifying antirheumatic drug (bDMARD) in PsA. However, up to 30% of patients receiving anti-TNF monotherapy fail to respond and require switching to a second TNF-inhibitor or bDMARD with a different mode of action. Strategies targeted at neutralizing IL-17A have been shown to have beneficial effects on skin, enthesitis, dactylitis and joint inflammation. Here, we explore the effect of neutralizing IL-17A versus anti-TNF on the expression of proinflammatory cytokines and metalloproteinases (MMPs) and whether dual-therapy targeting TNF and IL-17A may have superior activity than treatment with either agent alone.

Methods:

An allogeneic co-culture system was used comprising synovial fluid T helper (Th) memory cells and synovial fibroblasts (SF), derived from patients with active PsA. Anti-CD3/CD28 stimulation was used during culture, and anti-IL-17A antibody (Secukinumab), anti-TNFalpha antibody (Adalimumab), or the combination were added. PsA unstimulated synovial Th memory cells co-cultured with PsA SF were included as a control group as well as an isotype antibody control group. After 72 hours, supernatants were harvested for ELISA and cells were lysed for qPCR analysis.

Results:

Anti-TNF Ab treatment had no effect on IL-17A levels and neutralization of IL-17A did not influence the TNF production in the co-culture system. Both anti-TNF and anti-IL-17A single treatment significantly inhibited the production of IL-8 and reduced the mRNA expression of IL-1beta. Interestingly, neutralizing IL-17A resulted in a significant suppression of IL-6 levels which was not reduced by anti-TNF. Anti-TNF inhibited the production of MMP-3 and only the combination of anti-TNF and anti-IL-17A resulted in a significant suppression of MMP-1 levels and MMP-9 mRNA expression. MMP-13 mRNA expression was significantly suppressed by anti-TNF but not by anti-IL-17A, however, neutralizing both IL-17A and TNF showed a significant improvement in downregulating MMP-13 mRNA expression compared to single cytokine treatment. Moreover, anti-IL-17A reduced RANK mRNA expression that was significantly more suppressed compared to anti-TNF alone. However, no additive effect was noted for the combination blocking. Interestingly, only neutralizing both IL-17A and TNF significantly reduced the mRNA expression of RANKL. OPG mRNA expression was not influenced by anti-IL-17A and/or anti-TNF treatment.

Conclusion:

Neutralizing IL-17A or TNF in the PsA synovial T cell – SF co-culture system resulted in overlapping but also distinct effects on proinflammatory cytokine expression. TNF inhibition markedly suppress different MMPs with mostly an additional effect upon neutralization of IL17A. Neutralization both IL-17A and TNF is needed to downregulate RANKL expression which changes the RANKL/OPG balance. Together, these preliminary data suggest that dual therapy targeting IL-17A and TNF may be superior in their activity to protect against erosive arthropathy in PsA than treatment with either agent alone.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/distinct-and-overlapping-activities-of-il-17a-and-tnf-on-the-expression-of-proinflammatory-cytokines-and-mmps-in-psoriatic-arthritis-rationale-for-anti-il-17aanti-tnfalpha-combination-therapy/